The cannabinoid is a generic name of Δ9-tetrahydrocannabinol (abbreviated as Δ9-THC hereafter), which is a main ingredient of marijuana, which is made from hemp, and its analogues (Deway, Pharmacol. Rev., 38, 15-178 (1996)), and it is known as a substance which causes euphoria, sleepiness, hallucination, relief from mental tense, etc (Hollister, Pharmacol. Rev., 38, 1-20 (1986)).
Aside from the previous central effects, it is reported that the reactivity of lymphocytes is decreased in habitual users of marijuana (Naha et al., Science, 183, 419-420 (1974)), that marijuana or Δ9-THC lowers the ability of leucocytes migration and the function of macrophages in vitro (Schwartzfarb et al., J. Clin. Pharmacol., 14, 35-41 (1974); Lopez-Capero et al., J. Leuk. Biol., 39, 679-686 (1986)), and that it lowers the resistance to virus infection (Morahan etc., Infect. Immun., 23, 670-674 (1979)), etc. These facts imply that cannabinoids act not only on central nervous system but also on peripheral system (especially immune system).
The first reported cannabinoid receptor is the CB1 receptor, which was cloned from a rat cerebral cortex cDNA library in 1990 (Matsuda et al., Nature., 346, 561-564 (1990)). Afterwards, the CB2 receptor was cloned from a cDNA library of HL-60, a human promyelogenic leukemia cell line (Murano, et al., Nature., 365, 61-65 (1993)). It was revealed that the CB1 receptors are mainly expressed in brains and CB2 receptors in those cells which are responsible for immunity, e.g. splenic cells.
It had been conceived to adapt cannabinoids to medical care for a long time (Mechiulan, CRC Press, Boca Raton., 1-20 (1986); Razdan et al., Med. Res. Rev., 3, 119-146 (1983)), and some of them have already been used as medical drug such as Cesamet (Ward and Holmes, Drugs., 3, 127-144 (1985)). These are conceived to take effect via the CB1 receptor.
On the other hand, the physiological roles of the CB2 receptor, which is a peripheral receptor, is not revealed enough yet, but it is suggested that a compound which acts specifically on the CB2 receptor (agonist, antagonist) modulates inflammation and/or immune system. Moreover, it is expected that it is effective for an inflammation pain. (Calignano et al., Nature., 394, 277-281 (1998)).
From these evidences, those compounds which act on the CB2 receptor specifically, are useful for the prevention and/or treatment of various diseases such as asthma, nasal allergy, atopic dermatitis, autoimmune diseases, rheumatoid arthritis, immune dysfunction, postoperative pain, carcinomatous pain, etc.
Isoquinoline derivatives are known as follows: for example, in JP63-280069(A), it is disclosed that a compound of formula (A) (wherein AA is benzo or thieno and R2A and R3A are independently hydrogen or (C1˜5)alkyl, or taken together with the carbon atom to which they are attached to form 5 or 6 membered carbocycle and R11A is (C1˜4)alkyl, halogen, hydroxy and mA is 0, 1, 2 or 3 when AA is benzo, DA is IbA, etc.: R1A is hydrogen, (C1˜10)alkyl etc, R5′A is hydrogen or (C1˜4)alkyl, R4A is (C1˜4)alkoxy or —NR9AR10A (wherein R9A and R10A are independently hydrogen, C1˜12 branched or unbranched alkyl, alkenyl or alkynyl, etc., or R9A and R10A are taken together with the carbon atom to which they are attached to form pyrrolidinyl, piperidinyl, morpholinyl or piperazinyl, etc.)) has cardioprotective activity (groups are extracted for description).
Khim. Geterotsikl. Soedin., 946-949, 7, (1994) discloses a compound of 2-(3,3-dimethyl-3,4-dihydro-(2H)-isoquinoline-1-ylidene)-1-phenylmethan-1-one (Reg No. 163769-77-5).